Catechol diethers derivatives useful as pharmaceutical agents

ABSTRACT

A compound of formula (I) wherein a, b, V, W, X, Y, Z, R 1  and R 2  are as defined above. The compound of formula (I) and the pharmaceutically acceptable salts thereof are useful in inhibiting phosphodiesterase (PDE) type IV and the production of tumor necrosis factor (TNF) and in the treatment of asthma, arthritis, bronchitis, chronic obstructive airways disease, psoriasis, allergic rhinitis, dermatitis and other inflammatory diseases characterized by phosphodiesterase (PDE) type IV activity as well as AIDS, sepsis, septic shock and other diseases, such as cachexia, involving the production of TNF. ##STR1##

This application is a 371 of PCT/US95/07208 filed Jun. 7, 1995.

BACKGROUND OF THE INVENTION

This invention relates to catechol diethers containing a long lipophilicsidechain which are selective inhibitors of phosphodiesterase (PDE) typeIV or the production of tumor necrosis factor (TNF) and as such areuseful in the treatment of asthma, arthritis, bronchitis, chronicobstructive airways disease, psoriasis, allergic rhinitis, dermatitisand other inflammatory diseases as well as AIDS, sepsis, septic shockand other diseases, such as cachexia, involving the production of TNF.Compounds of the present invention may have combined PDE IV and TNFinhibitory activity.

This invention also relates to a method of using such compounds in thetreatment of the above diseases in mammals, especially humans and topharmaceutical compositions useful therefor.

Since the recognition that cyclic AMP is an intracellular secondmessenger (E. W. Sutherland, and T. W. Rall, Pharmacol. Rev., 1960, 12,265), inhibition of the phosphodiesterases has been a target formodulation and, accordingly, therapeutic intervention in a range ofdisease processes. More recently, distinct classes of PDE have beenrecognized (J. A. Beavo and D. H. Reifsnyder, TiPS, 1990, 11, 150), andtheir selective inhibition has led to improved drug therapy (C. D.Nicholson, R. A. Challiss and M. Shahid, TiPS, 1991, 12, 19). Moreparticularly, it has been recognized that inhibition of PDE type IV canlead to inhibition of inflammatory mediator release (M. W. Verghese etal., J. Mol. Cell Cardiol., 1989, 12 (Suppl. II), S 61) and airwaysmooth muscle relaxation (T. J. Torphy in Directions for New Anti-AsthmaDrugs, eds S. R. O'Donnell and C. G. A. Persson, 1988, 37,Birkhauser-Verlag). Thus, compounds that inhibit PDE type IV, but whichhave poor activity against other PDE types, inhibit the release ofinflammatory mediators and relax airway smooth muscle without causingcardiovascular effects or antiplatelet effects.

TNF is recognized to be involved in many infectious and auto-immunediseases, including cachexia (W. Friers, FEBS Letters, 1991, 285, 199).Furthermore, it has been shown that TNF is the prime mediator of theinflammatory response seen in sepsis and septic shock (C. E. Spooner etal., Clinical Immunology and Immunopathology, 1992, 62, S11).

SUMMARY OF THE INVENTION

The present invention relates to a compound of the formula ##STR2## andthe pharmaceutically acceptable salts thereof; wherein a is 0, 1, 2, 3or 4;

b is 0, 1, 2, 3 or 4;

V is O or S;

W is (C₂ -C₁₂)alkyl or (C₃ -C₁₂)alkenyl;

X is O or NR³ ;

Y is (C₁ -C₁₂)alkyl or (C₃ -C₁₂)alkenyl;

Z is (C₆ -C₁₀)aryl, (C₃ -C₇)cycloalkyl or a saturated or unsaturated (C₄-C₇) heterocyclic group containing as the heteroatom one or two of thegroup consisting of oxygen, sulphur, sulphonyl, nitrogen and NR⁴ whereinR⁴ is hydrogen or (C₁ -C₄) alkyl;

R¹ is (C₁ -C₄)alkyl;

R² is halo, (C₁ -C₄)alkyl or (C₁ -C₄)alkoxy; and

R³ is hydrogen of (C₁ -C₄)alkyl;

wherein each alkyl, alkoxy, cycloalkyl, aryl or heterocyclic group mayoptionally be substituted by 1 to 6 halo, (C₁ -C₄)alkyl,trifluoromethyl, hydroxy, (C₁ -C₄)alkoxy, cyano, nitro, (C₂ -C₄)alkenyl,(C₃ -C₆)cycloalkoxy, NR⁵ R⁶, CONR⁵ R⁶, CO₂ R⁶ and SO₂ NR⁵ R⁶ groupswherein R⁵ and R⁶ are each independently hydrogen or (C₁ -C₄)alkyl;

with the proviso the sum of the atoms defined by W, X and Y is 2 to 18.

The term "alkyl", as used herein, unless otherwise indicated, includessaturated monovalent hydrocarbon radicals having straight, branched orcyclic moieties or combinations thereof.

The term "alkoxy", as used herein, includes O-alkyl groups wherein"alkyl" is defined above.

The term "aryl", as used herein, unless otherwise indicated, includes anorganic radical derived from an aromatic hydrocarbon by removal of onehydrogen, such as phenyl or naphthyl.

The positions on the pyridinyl ring of formula I, as used herein, aredefined as follows: ##STR3##

The compounds of formula I include only those structures known to bestable to those skilled in the art.

Preferred compounds of formula I include those wherein b is 1.

Other preferred compounds of formula I include those wherein V is O.

Other preferred compounds of formula I include those wherein W is (C₄-C₈)alkyl, X is O and Y is (C₃ -C₇)alkyl.

Other preferred compounds of formula I include those wherein Z is (C₆-C₁₀)aryl.

Other preferred compounds of formula I include those wherein R¹ is (C₁-C₄)alkyl.

Other preferred compounds of formula I include those wherein a is 2 andR² is chloro in the 3 and 5 positions of the pyridinyl ring.

More preferred compounds of formula I include those wherein b is 1, V isO, W is (C₄ -C₈)alkyl, X is O, Y is (C₃ -C₇)alkyl, Z is (C₆ -C₁₀)aryl,R¹ is (C₁ -C₂)alkyl, a is 2 and R² is chloro in the 3 and 5 positions ofthe pyridinyl ring.

The present invention also relates to a method for the inhibition ofphosphodiesterase (PDE) type IV and the production of TNF comprisingadministering to a patient an effective amount of a compound accordingto formula I or a pharmaceutically acceptable salt thereof.

The present invention also relates to a method of treating aninflammatory condition in mammals which comprises administering to saidmammal an antiinflammatory amount of a compound of the formula I or apharmaceutically acceptable salt thereof.

The present invention also relates to a pharmaceutical composition forthe (a) treatment of asthma, arthritis, bronchitis, chronic obstructiveairways disease, psoriasis, allergic rhinitis, dermatitis and otherinflammatory diseases characterized by phosphodiesterase (PDE) Type IVactivity, AIDS, sepsis, septic shock and other diseases, such ascachexia, involving the production of TNF, or (b) the inhibition ofphosphodiesterase (PDE) type IV and the production of TNF comprising aneffective amount of a compound according to formula I or apharmaceutically acceptable salts thereof together with apharmaceutically acceptable carrier.

This invention also relates to a method of treating or preventing acondition selected from the group consisting of asthma, arthritis,bronchitis, chronic obstructive airways disease, psoriasis, allergicrhinitis, dermatitis and other inflammatory diseases, AIDS, septic shockand other diseases, such as cachexia, involving the production of TNFcomprising administering to a patient an effective amount of a compoundaccording to formula I or a pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION OF THE INVENTION

The following reaction schemes illustrate, but are not limited to, thepreparation of the compounds of the present invention. Unless otherwiseindicated a, b, V, W, X, Y, Z, R¹ and R² in the reaction Schemes and thediscussion that follow are defined as above. ##STR4##

In reaction 1 of Preparation A, the compound of formula XIII, wherein cis 1 to 10 and A is O or NR⁵ wherein R⁵ is a protecting group, such asbenzyl, is converted to the corresponding compound of formula XII byreacting XIII with a compound of the formula

    D--(CH.sub.2).sub.d --D                                    XX

wherein D is bromide, iodide, chloride, mesylate or tosylate and d is 2to 12, in the presence of a base, such as sodium hydride, and a polaraprotic solvent, such as tetrahydrofuran. The reaction mixture is heatedto a temperature between about 0° C. to about 100° C., preferably about62° C., for a time period between about 1 hour to about 24 hours,preferably about 12 hours.

In reaction 2 of Preparation A, the compound of formula XII is convertedto the corresponding compound of formula XI by reacting XII with a3-hydroxy4-alkoxybenzaldehyde compound in the presence of a base, suchas potassium carbonate, and a polar aprotic solvent, preferablydimethylformamide. The reaction is heated to a temperature between about0° C. to about 100° C., preferably about 80° C., for a time periodbetween about 1 hour to about 24 hours, preferably about 3 hours.

In reaction 1 of Preparation B, the compound of formula XV is convertedto the corresponding compound of formula XIV according the proceduresdescribed above in reaction 1 of Preparation A.

In reaction 1 of Preparation C, the compound of formula XV is convertedto the corresponding compound of formula XVII by reacting XV with acompound of the formula ##STR5## wherein D and d are as defined above,according the procedures described above in reaction 1 of Preparation A.

In reaction 2 of Preparation C, the compound of formula XVII isconverted to the corresponding compound of formula XVI by reacting asolution of XVII in a polar solvent, such as methanol, methylenechloride or a mixture thereof, with ozone gas at temperature betweenabout -80° C. to about -50° C., preferably about -78° C., until thesolution becomes saturated with ozone. The reaction mixture is thenpurged with an inert gas, such as nitrogen, and treated with a reducingagent, such as sodium borohydride.

In reaction 1 of Scheme 1, the 3-hydroxy-4-alkoxybenzaldehyde compoundof formula V is converted to the corresponding 4-alkoxybenzaldehydecompound of formula IV by alkylating V with a compound of the formula##STR6## wherein D is as defined above, in the presence of a base, suchas potassium carbonate, and a polar aprotic solvent, preferablydimethylformamide. The reaction is heated to a temperature between about0° C. to about 100° C., preferably about 80° C., for a time periodbetween about 1 hour to about 24 hours, preferably about 3 hours.

An alternative method for the synthesis of the 4-alkoxybenzaldehydecompound of formula IV is to react V with the compound of formula XIX,wherein D is hydroxy, under Mitsunobu conditions (Mitsunobu, O.,Synthesis, page 1 (1981)).

In reaction 2 of Scheme 1, the 4-alkoxybenzaldehyde compound of formulaIV is converted to the corresponding carboxylic acid of formula III byoxidizing IV with sodium chlorite in the presence of an olefin and apolar protic solvent, such as tertbutanol, as described in Tetrahedron,37, 2091 (1981). The carboxylic acid compound of formula III so formedis converted to the corresponding benzoyl chloride compound of formulaXXI, in reaction 3 of Scheme 1, by converting III to its correspondingcarboxylate and treating it with oxalyl chloride and a catalytic amountof dimethylformamide in a polar aprotic solvent, such as ether, asdescribed in Tetrahedron Letters, p. 3379 (1977).

In reaction 4 of Scheme 1, the benzoyl chloride compound of formula XXIis converted to the corresponding benzamide compound of formula II,wherein V is O, by reacting a 4-aminopyridine with a base, preferablysodium hydride, in a polar aprotic solvent, such as tetrahydrofuran, ata temperature between about 0° C. to about 60° C., preferably about 25°C., for a time period between about 30 minutes to about 3 hours,preferably about 30 minutes. A solution of the benzoyl chloride compoundof formula II in a polar aprotic solvent, such as tetrahydrofuran, isadded to the reaction mixture at a temperature of about 0° C. and thereaction mixture is then stirred at a temperature between about 0° C. toabout 40° C., preferably about 25° C., for a time period between about 1hour to about 24 hours, preferably about 16 hours. The benzamidecompound of formula II, wherein V is O, is converted to the thioamide offormula II, wherein V is S, by reacting II with phosphorus pentasulfidein a polar aprotic solvent, such as dioxane, as described in Synthesis,page 853 (1982).

In reaction 1 of Scheme 2, the alkyne compound of formula X is convertedto the corresponding compound of formula IX by reacting X with an arylhalide or aryl triflate and bis(triphenylphosphine)palladium chloride inan amine solvent, such as diethyl amine, as described in Bull. Chem.Soc. Jan., 63, 640 (1990).

In reaction 2 of Scheme 2, the benzaldehyde compound of formula IX isconverted to the corresponding carboxylic acid compound of formula VIIIaccording to the procedure described in reaction 2 of Scheme 1.

In reaction 3 of Scheme 2, the carboxylic acid compound of formula VIIIis converted to the corresponding compound of formula VII byhydrogenating VIII in the presence of a metal catalyst, such asplatinum, platinum oxide, Raney nickel, rhodium or palladium on carbon,and polar solvent, such as an alcohol, ethyl acetate, tetrahydrofuran,acetic acid or water or a mixture thereof. The reaction temperature isbetween about 20° C. to about 100° C. and the pressure of hydrogen isbetween about 1 atmosphere to about 10 atmospheres.

In reaction 4 of Scheme 2, the compound of formula VII is converted tothe corresponding benzamide compound of formula VI according to theprocedures described above in reactions 3 and 4 of Scheme 1.

The ability of the compounds or the pharmaceutically acceptable saltsthereof to inhibit phosphodiesterase IV (PDE₄) and, consequently,demonstrate their effectiveness for treating inflammatory diseases isshown by the following in vitro assay.

BIOLOGICAL ASSAY Human Eosinophil PDE₄

Human peripheral blood is collected in ethylenediaminetetraacetic acid,diluted 1:2 in piperazine-N,N'-bis-2-ethanesulfonic acid (PIPES) bufferand then layered over percoll solution. Gradients are formed bycentrifugation for 30 minutes at 2000 rpm at 4° C. The remainder of theisolation procedure, which is based on the procedure of Kita et al., J.Immunol., 152, 5457 (1994), is carried out at 4° C. Theneutrophil/eosinophil layer is collected from the percoll gradient andthe red blood cells are lysed. Remaining cells are washed in PIPES (1%FCS), incubated with anti-CD16 microbeads (MACS) for 1 hour, and passedover a magnetic column to remove the neutrophils. Eosinophils arecollected in the eluate and analyzed for viability by trypan blue andpurity by diff-quick stain. Eosinophil purity is routinely greater than99% using this method.

Purified eosinophils are resuspended in 750 μL of PDE lysis buffer (20mM triethylamine, 1 mM ethylenediaminetetraacetic acid, 100 μg/mlbacitracin, 2 mM benzamidine, 50 μM leupeptin, 50 μM PMSF, 100 μg/mlsoybean trypsin inhibitor) and quick frozen in liquid nitrogen. Cellsare thawed slowly and sonicated. Membranes are vortexed (disruption isconfirmed by Trypan blue staining of fragments). Disrupted cells arecentrifuged at 45 k rpm for 30 minutes at 4° C. to isolate membranes.Cytosol is decanted, and membrane resuspended to 200 μg/ml for use asPDE source in the hydrolysis assay yielding a window from 3000 to 5000counts.

Compounds are dissolved in dimethyl sulfoxide at 10-2M, then diluted1:25 in water to 4×10⁻⁴ M. This suspension is serially diluted 1:10 in4% dimethyl sulfoxide, for a final dimethyl sulfoxide concentration inthe assay of 1%.

Phosphodiesterase Inhibition Assay

To 12×75 mm glass tubes add:

25 μl PDE assay buffer (200 mM Tris/40 mM MgC12)

25 μl 4 nM/ml cAMP stock

25 μl test compound

25 μl PDE source (membrane)

Background control=membrane boiled 10 minutes

Positive control=25 μl unboiled membrane

Incubate 25 minutes in 37° C. water bath.

Reaction is stopped by boiling samples 5 minutes. Samples are applied toAffigel column (1 ml bed volume) previously equilibrated with 0.25 Macetic acid followed by 0.1 mMN-[2-hydroxyethyl]piperazine-N'-2-ethanesulfonic acid (HEPES)/0.1 mMNaCl wash buffer (pH 8.5). cAMP is washed off column with HEPES/NaCl,5'-AMP is eluted in 4 ml volumes with 0.25 M acetic acid. 1 ml of eluateis counted in 3 ml scintillation fluid for 1 minute [3H].

Substrate conversion=(cpm positive control×4)/total activity. Conversionrate must be between 3 and 15% for experiment to be valid.

% Inhibition=1-(eluted cpm-background cpm/control cpm-bkgd cpm)×100.

IC50s are generated by linear regression of inhibition titer curve(linear portion); and are expressed in μM.

TNF

The ability of the compounds or the pharmaceutically acceptable saltsthereof to inhibit the production of TNF and, consequently, demonstratetheir effectiveness for treating diseases involving the production ofTNF is shown by the following in vitro assay:

Peripheral blood (100 mls) from human volunteers is collected inethylenediaminetetraacetic acid (EDTA). Mononuclear cells are isolatedby Ficoll/Hypaque and washed three times in incomplete Hanks' balancedsalt solution (HBSS). Cells are resuspended in a final concentration of1×10⁶ cells per ml in pre-warmed RPMI (containing 5% FCS, glutamine,pen/step and nystatin). Monocytes are plated as 1×10⁶ cells in 1.0 ml in24-well plates. The cells are incubated at 37° C. (5% carbon dioxide)and allowed to adhere to the plates for 2 hours, after which timenon-adherent cells are removed by gentle washing. Test compounds (10 μl)are then added to the cells at 3-4 concentrations each and incubated for1 hour. Lipopolysaccharide (LPS) (10 μl) is added to appropriate wells.Plates are incubated overnight (18 hrs) at 37° C. At the end of theincubation period TNF was analyzed by a sandwich ELISA (R&D QuantikineKit). IC₅₀ determinations are made for each compound based on linearregression analysis.

Pharmaceutically acceptable salts of the acidic compounds of theinvention are salts formed with bases, namely cationic salts such asalkali and alkaline earth metal salts, such as sodium, lithium,potassium, calcium, magnesium, as well as ammonium salts, such asammonium, trimethyl-ammonium, diethylammonium, andtris(hydroxymethyl)-methylammonium salts.

Similarly acid addition salts, such as of mineral acids, organiccarboxylic and organic sulfonic acids e.g. hydrochloric acid,methanesulfonic acid, maleic acid, are also possible.

For administration to humans in the curative or prophylactic treatmentof inflammatory diseases, oral dosages of the compounds of formula I andthe pharmaceutically acceptable salts thereof (hereinafter also referredto as the active compounds of the present invention) are generally inthe range of from 0.1-400 mg daily for an average adult patient (70 kg).Thus for a typical adult patient, individual tablets or capsules containfrom 0.1 to 50 mg of active compound, in a suitable pharmaceuticallyacceptable vehicle or carrier. Dosages for intravenous administrationare typically within the range of 0.1 to 40 mg per single dose asrequired. For intranasal or inhaler administration, the dosage isgenerally formulated as a 0.1 to 1% (w/v) solution. The compound offormula I can also be administered topically in an ointment or cream inconcentrations of about 0.5% to about 1%, generally applied 2 or 3 timesper day to the affected area. In practice the physician will determinethe actual dosage which will be most suitable for an individual patientand it will vary with the age, weight and response of the particularpatient. The above dosages are exemplary of the average case but therecan, of course, be individual instances where higher or lower dosageranges are merited, and all such dosages are within the scope of thisinvention.

For administration to humans for the inhibition of TNF, a variety ofconventional routes may be used including orally, parenterally andtopically. In general, the active compound will be administered orallyor parenterally at dosages between about 0.1 and 25 mg/kg body weight ofthe subject to be treated per day, preferably from about 0.3 to 5 mg/kg.The compound of formula I can also be administered topically in anointment or cream in concentrations of about 0.5% to about 1%, generallyapplied 2 or 3 times per day to the affected area. However, somevariation in dosage will necessarily occur depending on the condition ofthe subject being treated. The person responsible for administrationwill, in any event, determine the appropriate dose for the individualsubject.

For human use, the active compounds of the present invention can beadministered alone, but will generally be administered in an admixturewith a pharmaceutical diluent or carrier selected with regard to theintended route of administration and standard pharmaceutical practice.For example, they may be administered orally in the form of tabletscontaining such excipients as starch or lactose, or in capsules orovales either alone or in admixture with excipients, or in the form ofelixirs or suspensions containing flavoring or coloring agents. They maybe injected parenterally; for example, intravenously, intramuscularly orsubcutaneously. For parenteral administration, they are best used in theform of a sterile aqueous solution which may contain other substances;for example, enough salts or glucose to make the solution isotonic.

The present invention is illustrated by the following examples, but itis not limited to the details thereof.

Preparation 1 4-Methoxy-3-(11-phenylundecyloxy)benzoyl chloride

To a magnetically stirred solution of4-methoxy-3-(11-phenylundecyloxy)benzaldehyde (2.4 grams) and2-methyl-2-butene (27 ml) in tert-butanol (50 ml) is added a solution ofsodium chlorite (4.5 grams) and sodium phosphate, monobasic (4.5 grams)in water (50 ml) over 10 minutes. After stirring for 1 hour at roomtemperature the volatile organics are removed under reduced pressure andthe resulting aqueous mixture is acidified to a pH of 1 with 1Nhydrochloric acid and extracted with ethyl acetate. The combinedorganics are washed with water and brine, dried over sodium sulfate andconcentrated under reduced pressure to give 2.3 grams of a yellow oil.

To a solution of the above oil in methanol (20 ml) at room temperatureis added sodium methoxide (0.3 grams). After 30 minutes the methanol isremoved under reduced pressure, anhydrous toluene is added and thenremoved under reduced pressure, anhydrous toluene is added and thenremoved under reduced pressure. The resulting white solid is suspendedin anhydrous ether (25 ml) at 0° C. under a nitrogen atmosphere andoxalyl chloride (20 ml) and dimethylformamide (1 drop) are added. Afterstirring for 1 hour at 0° C. the reaction mixture is filtered andconcentrated to a yellow oil (2.3 grams). This oil is used immediately.

Preparation 2 4-Methoxy-3-(11-phenylundecyloxy)benzaldehyde

To a solution of 3-hydroxy-4-methoxybenzaldehyde (2.5 grams),11-phenylundecylalcohol (4.6 grams) and triphenylphosphine (4.9 grams)in tetrahydrofuran at 0° C. is slowly added diethyl azodicarboxylate(2.9 ml). After stirring for 2 hours at room temperature the mixture isconcentrated under reduced pressure and purified by columnchromatography on a silica gel column using a 9:1 mixture of hexane andethyl acetate as eluent to give 2.4 grams of a yellow oil. ¹ H NMR(CDCl₃) δ ¹ H NMR (CDCl₃) δ 0.82-1.89 (m, 18H), 2.35-2.70 (m, 2H), 3.95(s, 3H), 4.00-4.08 (m, 2H), 6.95-7.45 (m, 8H), 9.84 (s, 1H).

Preparation 34-Methoxy-3-[6-(4-phenylbut-1-yloxy)hex-1-yloxy]benzaldehyde

To a stirred solution of 3-hydroxy-4-methoxybenzaldehyde (4.8 grams) indimethylformamide (100 ml) at room temperature is added potassiumcarbonate (4.9 grams) and 1-bromo-6-(4-phenylbut-1-yloxy)hexane (10.0grams). After stirring at 80° C. over 4 hours the reaction mixture ispoured into water and extracted with ethyl acetate. The combinedorganics are washed with 1N sodium hydroxide and brine, dried oversodium sulfate, filtered and concentrated under reduced pressure. Theresulting amber oil is filtered through a 5×10 cm pad of silica gel,eluting with a 1:3 mixture of ethyl acetate and hexane, to give 12.0grams of a colorless oil. MS (m/z) 384.

Preparation 4 4-Methoxy-3-[6-(6-phenylhex-1-yloxy)hex-1-yloxy]benzaldehyde

Reaction of 1-bromo-6-(6-phenylhex-1-yloxy)hexane and3-hydroxy-4-methoxy benzaldehyde analogous to the procedure ofpreparation 3, affords the title compound as a pale yellow oil. MS (m/z)413.

EXAMPLE 1N-(3,5-dichloropyrid-4-yl)-4-methoxy-3-(11-phenylundecyloxy)benzamide)

To a magnetically stirred suspension of 60% sodium hydride (60% inmineral oil) (0.53 grams) in anhydrous tetrahydrofuran (20 ml) at 0° C.is added a solution of 4-amino-2,5-dichloropyridine (0.90 grams) inanhydrous tetrahydrofuran (20 ml). After stirring for 30 minutes at roomtemperature the reaction mixture is cooled to 0° C. and treated with asolution of 4-methoxy-3-(11-phenylundecyloxy)benzoyl chloride (2.30grams) in tetrahydrofuran (20 ml). After stirring at room temperaturefor 16 hours the reaction mixture is poured into 50 ml of 1Nhydrochloric acid and extracted with ethyl acetate. The combinedorganics are washed with 1N hydrochloric acid, water and brine and thendried over sodium sulfate and concentrated under reduced pressure. Theresulting yellow solid is purified by column chromatography on a silicagel column using a ratio of 9:1 mixture of methylene chloride and ethylacetate as eluent to give 1.9 grams of an off-white solid. MP 114-5° C.;MS m/z 543, 545; Anal. calcd for C₃₀ H₃₆ Cl₂ N₂ O₃ : C, 66.29; H, 6.68;N, 5.15. Found: C, 6646; H, 6.61; N, 5.08

EXAMPLES 2-3

Reaction of the appropriate benzoyl chloride with4amino-2,5-dichloropyridine, analogous to the procedure of Example 1,affords the following compounds of formula II, wherein V is O, R¹ ismethyl, a is 2 and R² is chloro in the 3 and 5 positions on thepyridinyl ring.

    __________________________________________________________________________                         HRMS or  HRMS or Analysis                                      Analysis (calcd.) (found %CV, %H,                                         Ex#  W-[X-Y].sub.b -Z MP° C. MW %C, %H, %N %N                        __________________________________________________________________________    2   (CH.sub.2).sub.6 O(CH.sub.2).sub.4 -                                                  111-2                                                                              545.5                                                                             [M + H]545.1974                                                                        HRMS                                               phenyl    [M + H]545.1956                                                    3 (CH.sub.2).sub.6 O(CH.sub.2).sub.6 - 115-6 573.6 64.92, 6.68, 4.88                                      65.13, 6.60, 4.99                                  phenyl                                                                     __________________________________________________________________________

We claim:
 1. A compound of the formula ##STR7## or a pharmaceuticallyacceptable salt thereof; wherein a is 0, 1, 2, 3 or 4;b is 0, 1, 2, 3 or4; V is O or S; W is (C₂ -C₁₂)alkyl or (C₃ -C₁₂)alkenyl; X is O or NR³ ;Y is (C₁ -C₁₂)alkyl or (C₃ -C₁₂)alkenyl; Z is (C₆ -C₁₀)aryl, (C₃-C₇)cycloalkyl or a saturated or unsaturated (C₄ -C₇) heterocyclic groupcontaining as the heteroatom one or two of the group consisting ofoxygen, sulphur, sulphonyl, nitrogen and NR⁴ wherein R⁴ is hydrogen or(C₁ -C₄) alkyl; R¹ is (C₁ -C₄)alkyl; R² is halo, (C₁ -C₄)alkyl or (C₁-C₄)alkoxy; and R³ is hydrogen or (C₁ -C₄)alkyl;wherein each alkyl,alkoxy, cycloalkyl, aryl or heterocyclic group may optionally besubstituted by 1 to 6 halo, (C₁ -C₄)alkyl, trifluoromethyl, hydroxy, (C₁-C₄)alkoxy, cyano, nitro, (C₂ -C₄)alkenyl, (C₃ -C₆)cycloalkoxy, NR⁵ R⁶,CONR⁵ R⁶, CO₂ R⁶ and SO₂ NR⁵ R⁶ groups wherein R⁵ and R⁶ are eachindependently hydrogen or (C₁ -C₄)alkyl; with the proviso the sum of theatoms defined by W, X and Y is 2 to
 18. 2. A compound according to claim1, wherein b is
 1. 3. A compound according to claim 1, wherein V is O.4. A compound according to claim 1, wherein W is (C₄ -C₈)alkyl, X is Oand Y is (C₃ -C₇)alkyl.
 5. A compound according to claim 1, wherein Z is(C₆ -C₁₀)aryl.
 6. A compound according to claim 1, wherein R¹ is (C₁-C₂)alkyl.
 7. A compound according to claim 1, wherein a is 2 and R² ischloro in the 3 and 5 positions of the pyridinyl ring.
 8. A compoundaccording to claim 1, wherein b is 1, V is O, W is (C₄ -C₈)alkyl, X isO, Y is (C₃ -C₇)alkyl, Z is (C₆ -C₁₀)aryl, R¹ is (C₁ -C₂)alkyl, a is 2and R² is chloro in the 3 and 5 positions of the pyridinyl ring.
 9. Amethod for the inhibition of phosphodiesterase (PDE) type IV and theproduction of tumor necrosis factor (TNF) comprising administering to asubject an effective amount of a compound according to claim 1 or apharmaceutically acceptable salt thereof.
 10. A method of treating aninflammatory condition in mammals which comprises administering to saidmammal an antiinflammatory amount of a compound according to claim 1 ora pharmaceutically acceptable salt thereof.
 11. A method of treating acondition selected from the group consisting of asthma, arthritis,bronchitis, chronic obstructive airways disease, psoriasis, allergicrhinitis, dermatitis and other inflammatory diseases, AIDS, septic shockand cachexia, involving the production of TNF comprising administeringto a patient an effective amount of a compound according to claim 1 or apharmaceutically acceptable salt thereof.
 12. A pharmaceuticalcomposition for the (a) treatment of asthma, arthritis, bronchitis,chronic obstructive airways disease, psoriasis, allergic rhinitis,dermatitis and other inflammatory diseases which have phosphodiesterase(PDE) type IV activity, IDS, sepsis, septic shock and cachexia,involving the production of TNF, or (b) the inhibition ofphosphodiesterase (PDE) type IV and the production of tumor necrosisfactor (TNF) comprising a pharmaceutically effective amount of acompound according to claim 1 and a pharmaceutically acceptable carrier.